The present invention relates to novel polymeric platinum complex derivatives, preparation thereof, and use thereof. More particularly, the present invention relates to controlled releasing platinum complex derivatives incorporated in polyphosphazene, preparation thereof, and use thereof as an anticancer agent.
Among the known anticancer agents, cisplatin [cis-(NH.sub.3).sub.2 PtCl.sub.2 ], which was reported to exhibit high anticancer activity by Rogsenberg [B. Rosenberg, Nature 205, 698(1965)], was approved in 1979 by FDA of the United States as an anticancer agent, and has been used as one of the most effective chemotherapeutic agents against various cancers such as testicular cancer, ovarian cancer, bladder cancer, head and neck cancer or the like. However, the use of the drug is limited because of the high toxicity [LD.sub.50 =13 mg/kg, M. J. Cleare, Biochimie 60, 835(1978)].
Meanwhile, carboplatin [cis-(NH.sub.3).sub.2 Pt(CBDCA), wherein CBDCA represents 1,1-dicyclobutanedicarboxylate], which was approved by FDA in 1989 and has been used as a second-generation anticancer agent, has much lower toxicity than that of cicplatin. However, it has lower and narrower anticancer activity as well as high price, so that it cannot be widely used either.
Therefore, extensive researches for developing a third-generation anticancer agent having higher anticancer activity and lower toxicity than those of cisplatin have been performed worldwide, but in spite of such a great deal of efforts, commercialization of a third generation anticancer drug has not been successful so far.
Requirements for the third-generation platinum anticancer agent are excellent anticancer activity comparative to or higher than that of cisplatin and low toxicity comparative to that of carboplatin as well as wide therapeutic spectrum for the cancer treatment. In addition, it should have excellent activity to cancer cells resistant to cisplatin or carboplatin, showing no cross-resistance. Furthermore, the drug should have high water solubility and chemical stability. At present, ten or more candidate compounds are in clinical studies, but no drug has been successfully commercialized.
The anticancer activity and toxicity of the cisplatin analogs have not yet been clearly verified, but the research reports on this matter up to the present may be summarized as follows:
According to Pharmac. Ther. 25, 297 (1984) and Chem. Rev. 87, 1153 (1987), cisplatin administered into blood via intravenous injection or the like, exists mostly as neutral molecules without ionization because of the high chloride ion concentration (about 100 mM) in the blood plasma and easily diffuse through cell membrane. However, since the chloride ion concentration inside the cell is low (4 mM), the cisplatin molecules diffused into the cell are subjected to hydrolysis resulting in dissociation of chloride ions, amine-platinum cations thus formed are combined with DNA in the cell mostly via intrastrand cross-linking mode to inhibit the replication of DNA, whereby kill the cell. Like other anticancer drugs, platinum complex cannot distinguish cancer cells from the normal cells, leading to cytotoxicity. The oligomers produced by hydrolysis of cisplatin are also understood to cause various toxicities in body. However, concrete relationship between the molecular structures of the neutral amine ligand and the anionic leaving group of cisplatin molecule and the anticancer activity or toxicity in body has not yet been clarified.